The Role of DNA Looping in the Search for Specific Targets on DNA by Multisite Proteins

Many cellular processes involve simultaneous interactions between DNA and protein molecules at several locations. They are regulated and controlled by special protein-DNA complexes, which are known as synaptic complexes or synaptosomes. Because of the multisite nature of involved proteins, it was suggested that during the formation of synaptic complexes DNA loops might appear, but their role is unclear. We developed a theoretical model that allowed us to evaluate the effect of transient DNA loop formation. It is based on a discrete-state stochastic method that explicitly takes into account the free-energy contributions due to the appearance of DNA loops. The formation of the synaptic complexes is viewed as a search for a specific binding site on DNA by the protein molecule already bound to DNA at another location. It was found that the search might be optimized by varying the position of the target and the total length of DNA. Furthermore, the formation of transient DNA loops leads to faster dynamics if it is associated with favorable enthalpic contributions to nonspecific protein-DNA interactions. It is also shown that DNA looping might reduce stochastic noise in the system.